The present invention relates to a 1,4-dihydropyridine derivative, more particularly to a 4-(3-ethynyl)phenyl-1,4-dihydropyridine, a process for preparing the same and a pharmaceutical composition containing the same. The present invention is a useful invention in medical field.
Hitherto, many 1,4-dihydropyridine derivatives have been known as compounds having pharmacological activities such as vasodepressor activity and vasodilator activity. For example, it is known that dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (hereinafter referred to as "nifedipine") has strong pharmacological activities such as vasodepressor activity and coronary vasodilator activity (U.S. Pat. No. 3,644,627). Also, 2-(N-benzyl-N-methylamino)ethyl, methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydro chloride (hereinafter referred to as "nicardipine") (U.S. Pat. No. 3,985,758) and isopropyl, 2-methoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (hereinafter referred to as "nimodipine") are extensively known.
Most of well-known 1,4-dihydropyridine derivatives are compounds in which phenyl group at the 4-position of pyridine ring is substituted by nitro group, a halogen and the like. Examples of the compounds in which the phenyl group at the 4-position is substituted by acetylene are few. For example, with respect to the process for preparing 4-(2-ethynylphenyl)-2,6-dialkyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester which has been patented as a process, an alkyne group is exemplified as the substituent in a part of the process (Japanese Examined Patent Publication No. 12632/1976). However, the compound is not concretely described in which the phenyl group at the 4-position of pyridine ring is substituted by an alkyne group since no Example as to such compound is shown. Namely, physical property and pharmacological activity of such compound are unknown. Also, 4-[2-(2-aryl)ethynyl]phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxy lic acid dialkyl ester is disclosed in Japanese Unexamined Patent Publication No. 252768/1987. However, detailed pharmacological activity is not described. It is surmised that the use thereof as a medicament is an antihypertensive agent.
On the other hand, tissue selectivity and strength of activity of well-known cerebral function improvers are not sufficient. Therefore, because antihypertensive activity is a side effect for cerebral function improvers, a cerebral function improver had been desired which has weak antihypertensive activity and more superior tissue selectivity for cerebrum.
Calcium antagonists such as well-known 1,4-dihydropyridine derivatives as typical examples were drugs which have antihypertensive activity as main drug efficacy and cerebrocirculation improvement activity as secondary drug efficacy. In the treatment of a series of diseases which are generically named as cerebral failure and cerebral circulatory disturbance, antihypertensive activity is side effect rather than drug efficacy. The present invention provides a cerebral function improver which has superior tissue selectivity for cerebrum, weak antihypertensive activity and moreover has cerebroprotective activity, cerebroactivating activity and cerebrocirculation improvement activity.
As the result of the continuous effort and detailed investigation of pharmacological activity with respect to 1,4-dihydropyridine derivatives having phenyl group at the 4-position of pyridine ring substituted by acetylene group of the present inventors, now it has been found that compounds having superior tissue selectivity for cerebrum, weak antihypertensive activity, and moreover having cerebroprotective activity, cerebroactivating activity and cerebrocirculation improvement activity. Consequently, the present invention has been accomplished.
That is, in a series of diseases such as cerebral arterial sclerosis, cerebral hemorrhage, cerebral infarction and traumatic cerebral lesion, cerebrum becomes ischemic and cerebral nerve cells are excessively excited. The function of cerebral nerve cells is disturbed. Eventually it is considered that patients with the series of diseases fall into cerebral hypofunction, dysmnesia and dementia (See D. M. Woodbury, Psychiat. Neurol. Neurochir., 74, page 91, 1971). Also, it is considered that excessive excitation of cerebral nerve cells in case of ischemia is similar to excitation in case of ictus epilepticus. Therefore, a compound capable of inhibiting excessive excitation of cerebral nerve cells can be a preventive and therapeutic agent of the above-mentioned diseases as a cerebroprotective drug.
Flunarizine being a calcium antagonist which is regarded as highly specific for cerebrum is used as a cerebral circulation improver. However, it is reported that flunarizine induces side effects such as Parkinson symptom and depression symptom caused by central nervous system inhibitory activity when flunarizine is administered over an extended period of time (See Lugaresi A., Eur. Neurol., 28, pages 208-211, 1988). Accordingly, a cerebral function improver is desired which has accelative activity (cerebroactivating activity) rather than inhibitory activity for central nervous system without such side effects.
Cerebrocirculation improvement activity in case of ischemia is effective as a prevention and therapy of a series of diseases such as cerebral arterial selerosis, cerebral hemorrhage, cerebral infarction and traumatic cerebral lesion.
Thus it is possible that a compound having all of cerebroprotective activity, cerebroactivating activity and cerebrocirculation improvement activity becomes a superior cerebral function improver.
Concretely, as evaluation of cerebroprotective activity the compound of the present invention showed an effect equal to that of the antiepileptic agent diphenylhydantoin as a positive control in a test of convulsion induced by pentylenetetrazole in mice. The effect of the compound according to the present invention was stronger than those of nicardipine and nimodipine which are recognized as calcium antagonists having high selectivity for cerebrum. Also, in a test of maximal electroshock-induced seizures in mice it was recognized that the compound of the present invention was effective, and the compound of the present invention was stronger than flunarizine which is recognized as the well-known calcium antagonist having high selectivity for cerebrum. In the above test nimodipine was ineffective. As evaluation of cerebroactivating activity, in a forced swimming test in mice, although the compound of the present invention was effective, nimodipine and flunarizine were ineffective. Cerebrocirculation improvement activity was evaluated by decapitation induced hypoxia test in mice and a test of cerebrocortical blood flow increasing in rabbits. In the decapitation induced hypoxia test in mice, the compound of the present invention showed an effect equal to that of flunarizine and stronger effect than those of nimodipine and nicardipine. In the test of cerebrocortical blood flow increasing in rabbits, it was observed that the compound of the present invention showed stronger effect than that of flunarizine. Vasodepressor activity was evaluated in normal rats. Although nicardipine showed strong antihypertensive activity, on the contrary, in the compound of the present invention significant antihypertensive activity was not observed in a dose which shows the above-mentioned drug efficacy.
It is an object of the invention to provide a 1,4-dihydropyridine derivative having the formula (I) having all of cerebroprotective activity, cerebroactivating activity and cerebrocirculation improvement activity.
A further object of the invention is to provide processes for preparing the same.
It is a still further object of the invention to provide a composition containing the same useful for a superior cerebral function improver.
These and the other objects of the present invention will become apparent from the description hereinafter.